The establishment of dendrite morphology is crucial for normal neuronal communication in the brain. This process includes both the spatial and functional assembly of signal transduction machinery at synaptic sites and precise patterning of dendrites and their branches. Branching patterns, the relationship between the primary dendrites arising from the cell body and the secondary dendrites arising from primary dendrites, appear to be cell-type specific and play a role in determining how information is received and processed by a neuron. The amount of branches that a dendrite, or input center of a neuron, contains is thought to be directly related to learning and memory. In many learning disorders, such as autism, Rett syndrome, Down syndrome, Fetal Alcohol syndrome and Alzheimer's disease, patients show a reduced number of dendrite branches.
When there is an abnormal decrease in the number of dendrite branches on a neuron, the neuron cannot receive appropriate information, and hence disruption of proper signaling networks results (Vetter et al., 2001; Schaefer et al., 2003). Thus, there is a great interest in understanding how the number of dendrites produced by a neuron is determined.
A first step of elucidating the mechanism by which dendrite number is regulated is to identify the players in this process. Dendrite arbors are shaped by an interplay between intrinsic and extrinsic factors. Some of the known intrinsic factors are calcium/calmodulin-dependent protein kinase II (Fink et al., 2003), the small GTPases RhoA, Rac 1, and Cdc42 (Threadgill et al., 1997; Ruchhoeft et al., 1999; Li et al., 2000), novel genes identified in Drosophila (Gao et al., 1999; Moore et al., 2002; Grueber et al., 2003; Yu and Malenka, 2003; Emoto et al., 2004), β-catenin (Yu and Malenka, 2003), Dishevelled (Rosso et al., 2005), a calcium-responsive transactivator called CREST (Aizawa et al., 2004), and cypin (cytosolic PSD-95 interactor; (Firestein et al., 1999; Akum et al., 2004). The external factors comprise a long list and include neurotrophins (McAllister et al., 1995; McAllister et al., 1997; Baker et al., 1998; Horch et al., 1999; Lom and Cohen-Cory, 1999), electrical activity (McAllister et al., 1996; Cambiasso et al., 2000; Vaillant et al., 2002; Yu and Malenka, 2003) and estrogen (Cambiasso et al., 2000; Audesirk et al., 2003, 2003; Sakamoto et al., 2003; Dominguez et al., 2004; Nathan et al., 2004). As of yet, there have been only a small number of studies that examine how the extracellular and intrinsic factors are linked to determine dendrite morphology. The inventors have recently reported that cypin protein levels are increased in response to extracellular factors, such as KCI and NGF, that increase dendrite number (Akum et al., 2004).
Further, the inventors have found that cypin acts to increase dendrite number by binding to tubulin heterodimers and promoting microtubule assembly (Akum et al., 2004). The collapsin response mediator protein (CRMP) homology domain is responsible for this activity (Akum et al., 2004).
Since the understanding of the pathways by which dendrite number is regulated is crucial for proper diagnosis and treatment of learning disorders, such as autism, Rett syndrome, Down syndrome, Fetal Alcohol syndrome and Alzheimer's disease, it is necessary to identify proteins that interact with cypin and act to regulate dendrite number as part of a cypin protein complex.